The epithelial layer is both the site of attack and the first line of defense for most HIV infections. Unfortunately, this defense is breachable. Half of the 42 million people living with HIV are women infected vaginally and most of the remainder are men infected through the rectal epithelium. Fortification of these mucosal surfaces should be a priority for HIV vaccines. Cellular immunity plays a profound role in controlling disease progression but ultimately proves unsuccessful since it develops too slowly. Active local immunity could block the earliest infection events at mucosae and the spread of virus from these sites. While the generation of neutralizing antibodies against primary HIV isolates is problematic, several agents can reliably elicit the induction of cellular immunity. Since nasal immunization has often been shown to generate vaginal immune responses, we are proposing to explore the use of Listeria monocytogenes (Lm), an agent known to induce strong cellular immunity, as a nasal vaccine for HIV. One report has already shown that intranasal (IN) immunization with Lm is effective for generating resistance to high dose intranasal or intravenous Lm challenge. Our own preliminary studies confirm this, and show that the nasal mucosa is even more sensitive than the gut to infection and translocation by Lm. We propose to examine the early cellular immune responses to IN Lm infection and importantly, test both the safety of this approach and the prediction that the protective efficacy of IN immunization with live, attenuated Lm vaccine strains will extend to the female genital tract. In combination with oral inoculation, recombinant strains of Lm may result in protection of vaginal, intestinal and rectal surfaces against HIV infection.